There is now clear evidence that tumor tissues co-opt immune-checkpoint pathways to impair T cell ability to recognize and eliminate abnormal cancer cells. The clinical grade antibody, ipilimumab targeting the immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) was the first therapy to improve overall survival in patients with advanced melanoma. However, despite significant and long lasting remissions observed with CTLA4 blockade, responses remain limited to a subset of patients. In addition, although increasing doses of ipilimumab can significantly improve overall tumor responses, the therapeutic index of anti-CTLA4 mAb remains limited by the occurrence of immune-related adverse effects (irAE) that can be life threatening, unless promptly managed. Other irAE affect the skin, liver and the endocrine system. There is therefore an urgent need to develop novel strategies to not only increase, but to also uncouple, anti-tumor responses from unwanted immune related toxicities. Antitumor responses may be curtailed by alteration of T cell effector functions by an immunosuppressive tumor microenvironment despite the of CTLA4 blockade. T cell effector function is elicited in the lymph nodes (LN) and further modulated at local tissue sites by antigen presenting cells that include dendritic cells (DC) and macrophages (mph). Over the past decade, our group has been focusing on the mechanisms that control the homeostasis and function of DC and mph in normal and tumor tissues. Through this effort we discovered the instructive role played by the tissue environment in modulating DC and mph function. Specifically, we discovered that the cytokine GM-CSF, recently renamed Csf2, was produced by innate lymphocyte cells in the steady state gut in response to commensal signals to promote DC and mph production of retinoic acid and IL-10 that are necessary to induce intestinal T regulatory cell differentiation and expansion. These results extend previous studies by the Dranoff's laboratory showing that Csf2 drive DC and mph immunoregulation. Concomitantly, we and others have found that Csf2 controls the survival and function of cross-presenting cutaneous CD103+ DC and promotes vaccine CD8 cytotoxic immunity when combined with local tissue delivery of TLR agonists. Though on the one hand vaccine strategies utilizing Csf2-producing tumor cells have led to coordinated antitumor immune responses affecting substantial tumor destruction in patients, these successes has been tempered by the potential of Csf2 to promote tumor immunosuppressive effects. Our new results shed a new light into the mechanisms of action of Csf2-regulated immune responses and reveal that the dual regulatory and immunogenic role of Csf2 is dependent on both the tissue microenvironment in which it is produced and on the availability of DC activating signals. Our results also suggest that Csf2's compartmentalized role in tissue immunity could be exploited clinically to modulate CTLA4 outcome in cancer patients. Based on these results we hypothesize that By harnessing Csf2 compartmentalized role on tissue phagocyte function we could uncouple anti-tumoral effects from unwanted immune related toxicity induced by immune checkpoint blockade.